Adenosine can be considered to be a hormone which has been shown to have a number of significant effects on the mammalian central nervous system (CNS) [see, for example, Adenosine in the Nervous System (in the series Neuroscience Perspectives, Series Editor Jenner, P.) Stone, T. W., Ed., Academic Press Ltd., London, 1991, Annual Reports in Medicinal Chemistry, 1988, 23, 39-48; International Review of Neurobiology (Smythies, J. R. and Bradley, R. J., eds.) Academic Press Inc., 1985, 27, 63-139.], especially under conditions of neuronal stress where the compound appears to act as an endogenous neuroprotectant (Progress in Neurobiology, 1988, 31, 85-108, Trends in Pharmacological Sciences, 1988, 9, 193-194). For example, the concentration of adenosine has been demonstrated to rise greatly in certain brain regions following epileptic seizures or conditions of neuronal ischaemia/anoxia, (Brain Research 1990, 516, 248-256).
It has been established for some years now that centrally acting adenosine receptor agonists or compounds which increase extracellular adenosine levels can exhibit what is termed neuromodulator activity. Such substances influence the release of neurotransmitters in regions of the central nervous system (Annual Review of Neuroscience, 1985, 8, 103-124; Trends in Neurosciences, 1984, 164-168), with particular inhibitory effects on the release of the excitatory amino acid glutamic acid (glutamate) (Nature, 1985, 316, 148-150, Journal of Neurochemistry, 1992, 58, 1683-169).
There are several CNS ailments in which this adenosine receptor mediated neuromodulator activity may be of clear therapeutic benefit. Examples of these would include the treatment of convulsive disorders (European Journal of Pharmacology, 1991, 195, 261-265; Journal of Pharmacology and Experimental Therapeutics, 1982, 220, 70-76), prevention of neurodegeneration under conditions of brain anoxia/ischaemia (Neuroscience, 1989, 30, 451-462; Neuroscience Letters, 1987, 83, 287-293; Medical Hypotheses, 1990, 32, 45-49, Pharmacology of Cerebral Ischaemia 1990 (Kriegelstein, J. and Oberpichler, H., Eds., Wissenschaftliche Verlagsgesellschaft mbH: Stuttgart, 1990, pp 439-448) or the use of a purinergic agent in the treatment of pain (European Journal of Pharmacology, 1989, 162, 365-369; Neuroscience Letters, 1991, 121, 267-270). The relevance of adenosine and adenosine agonists to all these disease areas has recently been reviewed in Adenosine and Adenine Nucleotides as Regulators of Cellular Function (Phyllis, J. W., Ed., CRC Press Inc: Boca Raton, Fla., 1991, pp 319-400).
Adenosine receptors represent a subclass (P.sub.1) of the group of purine nucleotide and nucleoside receptors known as purinoreceptors. This subclass has been further classified into two distinct receptor types which have become known as A1 and A2. Extensive research has been carried out in a quest to identify selective ligands at these sites [see, for example, Comprehensive Medicinal Chemistry, Volume 3, (Hansch, C., Sammes, P. G. and Taylor, J. B., Pergamon Press PLC, 1990, 601-642)].
Selective ligands exist for A1 and A2 adenosine receptors and the structure-activity relationships of the various reference ligands have been reviewed (Biochemical Pharmacology, 1986, 35, 2467-2481) together with their therapeutic potential (Journal of Medicinal Chemistry, 1992, 35, 407-422). Among the known adenosine receptor agonists most selective for the A1 receptor over the A2 receptor are the examples where the adenine nucleus is substituted with a cycloalkyl group on the amino function, for example N-cyclopentyladenosine and N-cyclohexyladenosine (Journal of Medicinal Chemistry, 1985, 28, 1383-1384) or 2-chloro-N-cyclopentyladenosine (Naunyn-Schmiedeberg's Arch. Pharmacol. 1988, 337, 687-689).
Examples of adenosine derivatives in the chemical literature having a nitrogen bonded directly to the 6-amino substituent are few in number, and are summarized below.
They include N-aminoadenosine, N-[(N-methyl-N-phenyl)amino]adenosine (Journal of Medicinal Chemistry, 1985, 28, 1636-1643); N-(methylamino)adenosine and N-[(N-hydroxy-N-methyl)amino]adenosine (Journal of Medicinal Chemistry, 1968, 11, 521-523); 2-amino-N-aminoadenosine (Chemical and Pharmaceutical Bulletin, 1969, 17, 2373-2376); 2-fluoro-N-aminoadenosine (Journal of Medicinal Chemistry, 1970, 13, 427-430) and 2-fluoro-N-methoxyadenosine (Journal of Medicinal Chemistry, 1971, 14, 816-819). Finally, there is one example containing a cyclic amine, namely 2-amino-N-piperidinyladenosine (Arzneimittel-Forschung, 1970, 20, 1749-1751).
In the above scientific articles, no mention is made of any pharmacological effects of the compounds concerned on the central nervous system. In U.S. Pat. No. 3,819,613, substituted adenosine analogues with hydrazone derivatives on the 6-amino function are disclosed as hypotensive agents. In GB Patent No. 1,351,501, adenosine and 2-aminoadenosine derivatives having a --NH--R.sub.2 group joined to the 6-amino function are disclosed as coronary dilators and platelet aggregation inhibitors. In EP Publication No. 152,944A, a series of 2-, 6- and 8-substituted adenosine derivatives are described having activity as anti-allergy agents. In EP Publication No. 253,962A, adenosine and 2-haloadenosine analogues having an alkyl, cycloalkyl or an aralkyl group attached to the 6-amino function are described with activity as antidementia agents.
In EP Publication No. 402,752A, derivatives of adenosine unsubstituted in the 2-position are described which have a substituted heteroaromatic 1-pyrrolyl moiety attached to the 6-amino group. In PCT Publication No. WO 91/04032, methods of preventing neural tissue damage in neurodegenerative diseases by increasing extracellular concentrations of adenosine are described. Examples are given of prodrug esters of AICA riboside which are claimed to be centrally acting neuroprotective agents. In PCT Publication No. WO 92/02214, analogues of AICA riboside are described which increase extracellular adenosine levels with beneficial effects claimed in peripheral and CNS ischaemia. In PCT Publication No. WO 90/05526, 2-(alkyl-alkynyl)adenosine derivatives are described for treatment of ischaemic disease of the heart and brain. In EP Publication No. 0 423 777 A2 a method for treating gastrointestinal motility disorders using N(6) (substituted aminoalkyl) adenosine derivatives is disclosed. EP Publication No. 0 490 818 A1 describes a new use of 2'-O-methyl adenosine derivatives for a range of ailments including neurodegenerative disorders.
The present invention relates to new adenosine analogues having remarkably potent binding in vitro to the adenosine A1 receptor and at the same time showing selectivity for A1 receptor binding in vitro over that of the A2 receptor subtype. In addition, the compounds contained in this invention have a relatively high lipophilicity, especially when compared to adenosine analogues which are not substituted on the 6-amino group or the purine 2-position. This latter property makes these compounds suitable for passage across the blood brain barrier, and supports the suggestion that the compounds may be candidate drugs for the CNS ailments mentioned within this invention.
The possibility that some of the compounds may be substrates for nucleoside-specific active transport systems across the blood barrier is, however, not excluded. These useful properties support the suggestion that the compounds may be candidate drugs for the CNS ailments mentioned above in humans. There are instances where it has been demonstrated that co-administration of a peripherally active adenosine receptor antagonist can lower the expected side effects on the cardiovascular system when an adenosine agonist is used as a neuroprotectant in animal models (Journal of Molecular Neuroscience, 1990, 2, 53-59). This method of lowering side-effects is also applicable during the therapeutic use of the adenosine receptor agonists covered by the present invention.
The novel compounds of the invention are purine derivatives of formula (I), or a pharmaceutically acceptable salt thereof: ##STR2## wherein X is halogen, perhalomethyl, cyano, C.sub.1-6 -alkoxy, C.sub.1-6 -alkylthio or C.sub.1-6 -alkylamino;
R.sup.1 is selected from the groups consisting of ##STR3## wherein n is 1 to 3 and where the group (a) may be optionally substituted with one or two C.sub.1-6 -alkyl groups, C.sub.2-6 -alkenyl, C.sub.2-6 -alkynyl, phenoxy, phenylsulphonyl, phenylthio, hydroxy, phenyl, C.sub.1-6 -alkoxy or C.sub.1-6 -alkoxy-C.sub.1-6 -alkyl, phenylthioalkyl or ##STR4## wherein Y is O, S or NZ, where Z is H, C.sub.1-6 -alkyl or phenyl, and where the group (b) may be optionally substituted with C.sub.1-6 -alkyl, C.sub.2-6 -alkenyl, C.sub.2.6 -alkynyl, phenoxy, phenyl, C.sub.1-6 -alkoxy or C.sub.1-6 -alkoxy-C.sub.1-6 -alkyl, or ##STR5## which may be optionally substituted with C.sub.1-6 -alkyl, C.sub.2-6 -alkenyl, C.sub.2-6 -alkynyl, phenoxy, phenylthio, phenyl, C.sub.1-6 -alkoxy or C.sub.1-6 -alkoxy-C.sub.1-6 -alkyl.
In certain examples, the group R.sup.1 can contain one or more asymmetric carbon atoms in addition to those asymmetric centres already present in the molecule. In examples where this is the case, this invention includes all resulting diastereoisomers and mixtures thereof.
Various salts of compounds of formula (I) can be prepared which can be considered physiologically acceptable. These include addition salts derived from inorganic or organic acids, for example, acetates, fumarates, glutarates, glutaconates, lactates, maleates, methanesulphonates, phosphates, salicylates, succinates, sulphates, sulphamates, tartrates and paratoluenesulphonates. In some cases, solvates of either the free nucleosides or the acid addition salts can be isolated and these solvates may, for example, be hydrates or alcoholates.
Compounds of formula (I), which act as adenosine receptor agonists, are found to be useful in the treatment of central nervous system conditions such as neuronal ischaemia/anoxia, convulsive disorders (epilepsy) and neurodegeneration. This includes treating disorders where the blood flow to the brain is interrupted, for example during traumatic head injury, cardiac arrest and stroke.
Further, the compounds of formula (I) are found to be useful as analgesic agents, in lowering plasma FFA levels or as cardiovascular agents.
The invention also relates to methods of preparing the above mentioned compounds. These methods comprise: